U.S. Pat. No. 5,532,241 (hereinafter referred to as the '241 patent) discloses a variety of piperidine and piperazine derivatives and their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are active on the central nervous system, especially in terms of 5-HT1A-agonist and 5-HT-reuptake inhibition. They are furthermore active as serotonin agonists and antagonists. These compounds and their physiologically acceptable acid addition salts can, therefore, be used as active ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics, and antihypertensives. Among them, Vilazodone hydrochloride, 5-[4-[4-(5-Cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxamide hydrochloride, is a serotonergic antidepressant that is used for the treatment of major depressive disorder (MDD). Vilazodone hydrochloride is represented by the following structural formula:

Vilazodone hydrochloride was approved by the FDA for use in the United States to treat major depressive disorder and it is sold under the trade name VIIBRYD™. It is orally administered as tablets containing 10 mg, 20 mg and 40 mg of vilazodone as the hydrochloride salt.
Various processes for the preparation of benzofuran-2-carboxamide derivatives, preferably vilazodone, their intermediate compounds, and their pharmaceutically acceptable salts are apparently disclosed in U.S. Pat. No. 5,532,241, U.S. Pat. No. 5,723,614, U.S. Pat. No. 5,977,112, U.S. Pat. No. 5,418,237 and U.S. Pat. No. 7,799,916; U.S. Patent Application Publication No. 2010/0036139A1; Chinese Patent Application Publication Nos. CN 102267932, CN 102267985, CN 102180868, CN 102796037, CN 102875538, CN 102659660 and CN102617558 and Journal of Medicinal Chemistry, 2004, Vol. 47, No. 19, pages 4684-4692; Drugs of the Future 2001, 26(3), 247, and Liebigs Ann. Chem. 1988, 749-752.
U.S. Pat. No. 5,532,241 (hereinafter referred to as the '241 patent) describes several synthetic routes for preparing vilazodone. According to one synthetic process, vilazodone is prepared by the condensation of 5-(1-pipearzinyl)benzofuran-2-carboxamide with 3-(4-chlorobutyl)-1H-indole-5-carbonitrile. According to another synthetic process, vilazodone is prepared by reacting 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylic acid with 2-chloro-1-methylpyridinium methanesulfonate in the presence of N-methylpyrrolidone to produce a reaction mass, followed by treatment with dried ammonia gas and subsequent working up to produce vilazodone. The synthetic routes are depicted in scheme 1:

Similar process for the preparation of vilazodone is also reported in Journal of Medicinal Chemistry, 2004, Vol. 47, No. 19, pages 4684-4692 (hereinafter referred to as the ‘JMC article’). As per the process reported in the JMC article (see column-1 of Page No. 4690), the vilazodone is prepared by reacting 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylic acid with 2-chloro-1-methylpyridinium iodide in the presence of N-methylpyrrolidone to produce a reaction mass, followed by drop wise addition of ethyldiisopropyl amine while introducing ammonia gas and subsequent work up to produce vilazodone. The resulting vilazodone free base is then converted into its hydrochloride salt by dissolving vilazodone free base in hot 2-propanol to form a solution, followed by slow addition of HCl-saturated 2-propanol at room temperature until complete precipitation occurs to yield vilazodone hydrochloride (Melting Point: 277-279° C.).
The ‘JMC’ Article also describes a process for the preparation of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile as depicted in scheme 2:

As per the process described in the JMC Article, 3-(4-chlorobutyl)-1H-indole-5-carbonitrile is prepared by reacting 5-cyanoindole with 4-chlorobutyryl chloride in the presence of isobutyl-AlCl2 to produce 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile, which is then subjected to selective desoxygenation of the keto function with sodium bis(2-methoxyethoxy)aluminum hydride (Vitride/Red-Al) to produce the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile.
According to U.S. Pat. No. 5,418,237 (hereinafter referred to as the '237 patent) & the Research Article ‘Drugs of the Future 2001, 26(3), 247’, 3-(4-chlorobutyl)-1H-indole-5-carbonitrile is prepared by reacting 5-cyanoindole with 4-chlorobutyryl chloride to give 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile, which then reduced with diborane to produce the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile.
The processes for the preparation of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile described in the aforementioned prior art suffer from disadvantages that the processes involve the use of highly dangerous, highly flammable and expensive reducing agents like diborane and bis(2-methoxyethoxy)aluminum hydride (Vitride/Red-Al), which are very difficult to handle at lab scale and commercial scale operations. Therefore, the use of these reducing agents is not advisable for scale up operations.
According to U.S. Pat. No. 6,509,475 B1 (hereinafter referred to as the '475 patent), it was not possible to isolate 3-(4-chlorobutyl)-1H-indole-5-carbonitrile when Lithium aluminium hydride (LiAlH4) or Sodium borohydride with boron trifluoride etherate (NaBH4/BF3 ether) is used as a reducing agent for the reduction of 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile.
U.S. Pat. No. 5,723,614 (hereinafter referred to as the '614 patent) discloses a process for the preparation of 5-(1-pipearzinyl)benzofuran-2-carboxamide. The synthesis is depicted in scheme 3:

According to the '614 patent, the preparation of 5-(1-pipearzinyl)benzofuran-2-carboxamide is carried out in four steps starting from ethyl 5-aminobenzofuran-2-carboxylate. According to first step, ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is prepared by reacting ethyl 5-aminobenzofuran-2-carboxylate with N,N-bis(2-chloroethyl)amine in dichloromethane to produce a reaction mass, followed by customary work-up using a solvent system (isopropanol/water 95:5). According to second step, the ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is subjected to BOC protection by reacting with di-tert-butyl dicarbonate in tetrahydrofuran to produce ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-caboxylate. In third step, the ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-caboxylate is reacted with formamide in the presence of sodium alkoxide in N-methylpyrrolidone to produce 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide. In fourth step, the 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide is then deprotected with methanolic HCl to produce the 5-(1-pipearzinyl)benzofuran-2-carboxamide.
Similar process for the preparation of ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is also reported in the JMC article. As per the process reported in the JMC article, the ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is prepared by heating a suspension of ethyl 5-aminobenzofuran-2-carboxylate, bis(2-chloroethyl)ammonium chloride and potassium carbonate to reflux temperature in 1-butanol for 48 hours. The hot suspension is decanted and filtered, followed by evaporation and subsequent recrystallization of the crude product using methanol to produce the ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate as a hydrochloride salt with 27% yield.
The processes for the preparation of vilazodone and its intermediates described in the aforementioned prior art suffer from disadvantages such as the use of additional and expensive reagents like 2-chloro-1-methylpyridinium methanesulfonate, 2-chloro-1-methylpyridinium iodide, di-tert-butyl dicarbonate, ethyldiisopropyl amine, formamide and sodium alkoxide; use of expensive and hazardous solvents like N-methylpyrrolidone, 1-butanol and tetrahydrofuran; use of tedious and cumbersome procedures like multiple process steps, prolonged reaction time periods, column chromatographic purifications, multiple isolations/re-crystallizations, and thus resulting in a poor product yield and quality. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
CN 102267932 A (hereinafter referred to as CN'932 publication), describes a process for the preparation of vilazodone as depicted in scheme 4:

As per the process described in CN'932 publication, vilazodone is prepared by reacting 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile with sodium borohydride in isopropanol at reflux temperature, followed by treating the reaction mass with dilute hydrochloric acid and subsequent workup and then subjecting to column chromatography purifications to produce 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile. The hydroxylbutyl intermediate obtained is then subjected to sulfonylation using a sulfonylating agent selected from p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride to produce corresponding sulfonylated intermediate, which is then condensed with 5-(1-piperazinyl)benzofuran-2-carboxamide in acetonitrile to produce vilazodone.
The processes for the preparation of vilazodone and its intermediates described in CN'932 publication suffer from several drawbacks since the processes are not reproducible and they involve expensive column chromatographic purifications, and the yields of vilazodone and its intermediates obtained are very low. Moreover, the vilazodone and its intermediates obtained by the processes described in the CN'932 publication do not have satisfactory purity.
The present inventors have tried to reproduce the processes exemplified in the CN'932 publication. As a result, it has been found that most of the reactions described/exemplified in the CN'932 publication do not go to completion. For example, the reaction of 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile with sodium borohydride in isopropanol as described in the CN'932 publication (Example 1 in page 8) does not end up with the formation of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile since this reaction is practically and theoretically impossible. Moreover, it has been observed by the present inventors that the condensation reaction between the 3-[4-(p-toluenesulfonyloxy)butyl]-1H-indole-5-carbonitrile and 5-(1-piperazinyl)benzofuran-2-carboxamide in acetonitrile exemplified in Example 6 of CN'932 publication does not go to completion even after maintenance of prolonged time periods.
U.S. Pat. No. 7,799,916 (hereinafter referred to as U.S. Pat. No. '916 patent), describes two processes for the preparation of vilazodone as depicted in scheme 5:

According to first synthetic route described in U.S. Pat. No. '916 patent, vilazodone is prepared by reacting 5-bromo-benzofuran-2-carboxamide with 3-(4-piperazin-1-ylbutyl)indole-5-carbonitrile in the presence of highly expensive reagents including tris(dibenzylidene acetone)dipalladium, tris-tert-butylphosphine, sodium tert-butoxide, and diethylene glycol dimethyl ether to produce a yellow-grey suspension, which is then heated at 120° C. for 48 hours, followed by cooling the reaction mass to room temperature and then subjecting the resulting mass to conventional working up to produce vilazodone fee base.
According to another synthetic process described in U.S. Pat. No. '916 patent, vilazodone is prepared by reacting 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile with sulfur trioxide/pyridine complex in dimethylsulfoxide to produce a reaction mass, followed by customary work up and then concentrating the resulting mass to produce an oily residue. The resulting residue is then chromatographed on silica gel using a mixture of dichloromethane and methyl tert-butyl ether to produce 3-(4-oxobutyl)-1H-indole-5-carbonitrile. The oxobutyl compound is reacted with 5-(1-piperazinyl)benzofuran-2-carboxamide in the presence of sodium cyanoborohydride to produce vilazodone free base, which is further treated with aqueous hydrochloric acid to produce vilazodone hydrochloride.
The processes for the preparation of vilazodone and its intermediates as described in the aforementioned prior art suffer from the following disadvantages and limitations:    a) the prior art processes involve the use of highly flammable and dangerous reagents like isobutyl-AlCl2 (DIBAL), sodium bis(2-methoxyethoxy)aluminum hydride (Vitride/Red-Al), diborane, Lithium aluminium hydride (LiAlH4) and boron trifluoride etherate (NaBH4/BF3 ether);    b) handling of the aforesaid reducing agents is very difficult at lab scale and in commercial scale operations;    c) the processes require longer reaction times and the yields and purity of the product obtained are very low;    d) the processes involve the use of highly hazardous and expensive reagents and solvents like 2-chloro-1-methylpyridinium methanesulfonate, 2-chloro-1-methylpyridinium iodide, N-methylpyrrolidone, di-tert-butyl dicarbonate, tris(dibenzylidene acetone)dipalladium, tris-tert-butylphosphine, diethylene glycol dimethyl ether, sulfur trioxide/pyridine complex and dimethylsulfoxide;    e) the processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolation/re-crystallizations;    f) methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible;    g) the overall processes generate a large quantity of chemical waste which is difficult to treat.
Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of vilazodone and its intermediates at lab scale and in commercial scale operations.
A need remains for novel, commercially viable and environmentally friendly processes of preparing vilazodone and its intermediates with high yield and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced process steps, reduced reaction time periods, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of vilazodone and its intermediates in high purity and with high yield.